RETRACTED. 186 Self-Assessment examination

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1 186 Self-Assessment examination inance (in contrast to the classic infantile hemangiomas, which are more common in females). The most common location is the head and neck area, followed by the extremities and trunk. It is histologically characterized by lobules of small blood vessels separated by dense fibrous tissues, epidermal atrophy, and a loss of dermal appendages. The intralobular endothelial cells display plump hyperchromatic nuclei protruding into the lumen, resembling a hobnailed appearance. There are hemosiderin deposits in the thickened dermis with a slight increase of mast cells as well as small foci of calcifications. The proliferative phase of NICH occurs prenatally and it becomes fully developed at birth. However, it does not undergo involution. As a result, surgery might be regarded as the treatment of choice with no tendency to recur. Both RICH and NICH can be characteristically distinguished from the congenital infantile hemangioma by their negativity of glucose transporter- 1 (GLUT-1) and Lewis Y Antigen (LeY) immunoactivity. For this series, the recommended choices are as follows: 1, d; 2, e; 3, a; 4, b; 5, e; 6, c; 7, e; 8, a. BIBLIOGRAPHY Enjolras O, Mulliken JB, Boon LM, Wassef M, Kozakewich HP, Burrows PE. Noninvoluting congenital hemangioma: a rare cutaneous vascular anomaly. Plast Reconstr Surg 2001;107: Konez O, Burrows PE, Mulliken JB, Fishman SJ, Kozakewich HP. Angiographic features of rapidly involuting congenital hemangioma (RICH). Ped Radiol 2003;33:15-9. North PE, Waner M, James CA, Mizeracki A, Frieden IJ, Mihm MC Jr. Congenital nonprogressive hemangioma: a distinct clinicopathologic entity unlike infantile hemangioma. Arch Dermatol 2001;137: Rogers M, Lam A, Fischer G. Sonographic findings in a series of rapidly involuting congenital hemangiomas (RICH). Ped Dermatol 2002;19:5-11. Man with whitish papule on ear Carlos Rodriguez, MD, a and Amor Khachemoune, MD, CWS, b Chicago, Illinois, a and Boston, Massachusetts b A 59-year-old white man presented with 3 discrete, firm, asymptomatic, 5-mm to 8-mm white to yellow papules on the helices of his ears, reportedly present for more than 1 year (Figs 3 and 4). 9. The differential diagnosis includes all of the following except (Choose single best response). a. calcinosis cutis b. xanthoma c. gouty tophus d. molluscum contagiosum e. cutaneous leishmaniasis The patient denied any foreign travel. On further questioning, he reported that his father had died from complications of high serum uric acid. 10. The most likely diagnosis is (Choose single best response). a. calcinosis cutis b. xanthoma c. gouty tophus d. molluscum contagiosum e. cutaneous leishmaniasis 11. This disease is also known as (Choose single best response). a. The Disease of Kings b. Pharaoh s disease c. Vegetarian s disease d. Mal de Meleda e. Espundia 12. In which of the following patients would gout most likely be encountered? (Choose single best response.) a. 33-year-old white female b. 50-year-old white male c. 47-year-old African American male d. 35-year-old African American female e. 10 year-old obese Hispanic male

2 VOLUME 53, NUMBER 1 Self-Assessment examination Which of the following mechanisms is most commonly responsible for development of primary gout? a. Under-excretion of uric acid by the kidney b. Medication-induced overproduction of uric acid c. Overproduction of uric acid caused by psoriasis d. Overproduction of uric acid caused by genetic enzyme deficiencies e. Alcohol-induced degradation of ATP 14. Which of the following is the most frequent cause of secondary gout? (Choose single best response.) a. Alcohol abuse b. Diuretic therapy c. Obesity d. Diabetes mellitus e. Glucose-6-phosphatase deficiency 15. Each of the following diseases predisposes to gouty attacks except a. Lesch-Nyhan syndrome b. type 1 glycogen storage disease (von Gierke disease) c. psoriasis d. Turner syndrome e. chronic myelogenous leukemia 16. Which of the following tests is essential in diagnosing gout? a. Radiograph(s) of affected joint(s) b. 24-hour urinary uric acid level c. Biopsy of involved skin d. Serum uric acid level e. Synovial fluid analysis of affected joint(s) 17. The development of urate crystal deposits (tophi) generally occurs how long after the onset of gout? a. \6 months b. 1-3 years c. 5-7 years d. [10 years e. Prior to the onset of gout 18. Urate crystals are believed to induce inflammation primarily by stimulating production of which of the following mediators? (Choose single best response.) a. Interleukin-1 b. Interleukin-2 c. TNF-alpha d. Interleukin-6 e. TNF-gamma 19. Each of the following is a common site for tophi deposition except a. first metatarsophalangeal joint b. helix of the ear c. tongue d. Achilles tendon e. olecranon 20. Podagra may also be observed in association with each of the following diseases except a. pseudogout b. psoriatic arthritis c. sarcoidosis d. gonococcal arthritis e. syphilis 21. Each of the following characteristics is common to urate crystals upon microscopic examination of aspirated synovial fluid except (Choose single best response.) a. positive birefringence under polarized light b. monosodium urate monohydrate composition c. needle-shaped d. water-soluble e. yellow or blue color 22. Which of the following agents should be used in fixation of suspected gouty tophi for histologic analysis? a. Methanol b. Potassium hydroxide c. Formalin d. Osmium tetroxide e. 95% ethanol 23. Which of the following is true regarding dermal and subcutaneous tissue inflammation in comparison to epidermal inflammation in tophaceous gout? a. More inflammation is noted b. Less inflammation is noted c. Inflammation is absent d. Equal amounts of inflammation are noted e. There is no predictable pattern of inflammation 24. Which of the following may be used to stain urate crystals brown/black in histologic specimens? a. Hematoxylin-eosin b. Cresyl violet c. Iron stain d. De Galantha e. Pyronin G

3 188 Self-Assessment examination 25. Which of the following tests can easily be used to differentiate gouty tophi from rheumatoid nodules? a. Plain radiograph b. Ultrasound examination c. CT scan d. Serum uric acid measurement e. Serum rheumatoid factor measurement 26. Each of the following agents is used to treat acute gout except a. NSAIDs b. prednisone c. allopurinol d. colchicine e. ACTH 27. Which of the following agents is most effective in decreasing uric acid synthesis in gout prophylaxis? a. Sulfinpyrazone b. Allopurinol c. Probenecid d. Colchicine e. Corticosteroids 28. Increased incidence of rash occurs in patients taking allopurinol concurrently with which of the following drugs? a. NSAIDs b. Sulfinpyrazone c. Colchicine d. Ampicillin e. Thiazide diuretics Discussion Gout has been known as the Disease of Kings and the King of Diseases, because Kings Henry VIII and Louis XIV, as well as other prominent historical figures, had gout. The most characteristic lesion of gout is the tophus, a soft tissue deposit of monosodium urate crystals that triggers a severe inflammatory reaction in the surrounding tissue. Although the first metatarsophalangeal joint is the most common site of initial inflammatory disease (podagra), visible tophi can also develop on the helix of the ear, olecranon bursa, Achilles tendon, extensor surface of the forearm, prepatellar bursa, fingertips, and toes. Less commonly, tophi may develop on the tongue, vocal cords, epiglottis, and penis. Podagra itself may also be seen in other disease states including pseudogout, sarcoidosis, psoriatic arthritis and gonococcal arthritis. Gout can arise from metabolic deficits that cause uric acid overproduction or from renal underexcretion of urates (primary gout), or it may be caused by hyperuricemia induced by coexisting disease or medications (secondary gout). Primary gout more commonly affects men, with the first attack occurring typically between the ages of 40 and 50 years, and with African Americans having a slightly higher prevalence than whites. It is uncommon in premenopausal women, and some speculate that estrogen expedites renal excretion of uric acid. The majority of patients with primary gout have tubular defects that reduce uric acid excretion; excessive de novo synthesis is seen in only 10% of patients. Secondary gout most commonly develops because of diuretic therapy, and may also occur in patients receiving photochemotherapy. Metabolic disorders that predispose to gout are those that alter purine metabolism, including deficiencies in glucose-6-phosphatase (as in type 1 glycogen storage disease), hypoxanthine-guanine phosphoribosyl transferase (HGPRT; severe deficiency is seen in Lesch-Nyhan syndrome) and overactivity of phosphoribosyl pyrophosphate synthetase (PRPP; inherited as an X-linked trait). Other factors that may contribute to the development of gout include alcohol abuse, hypertension, obesity, insulin resistance, high-purine diet, and lead exposure. Medications that decrease urate excretion include thiazide diuretics, salicylates, ethambutol, and cyclosporine. Secondary hyperuricemia may also develop because of myeloproliferative diseases, as well as severe psoriasis and other diseases with high tissue nucleic acid turnover. Gout progresses in 4 clinical stages: 1. Asymptomatic hyperuricemia: Serum uric acid level [7 mg/dl (normal ranges: men, 4-6 mg/dl; women, 3-5 mg/dl). Asymptomatic hyperuricemia does not require treatment; high levels may be detected in 5% of adults, and only a minority of those with hyperuricemia develop gout. In general, uric acid levels are elevated for [20 years prior to the onset of gout. Hyperuricemia may be suggestive of gout, but not diagnostic in the absence of characteristic clinical findings. 2. Acute gout: Hyperuricemia causes the precipitation of uric acid crystals from supersaturated extracellular fluid. A brisk inflammatory response develops, causing abrupt onset of pain and swelling, commonly occurring at night or in the early morning hours. The local inflammation may be

4 VOLUME 53, NUMBER 1 Self-Assessment examination 189 accompanied by fever, leukocytosis, and an elevated erythrocyte sedimentation rate, and less commonly by hemolytic anemia, calcium level abnormalities, or hypothyroidism. Urate crystals stimulate monocyte and macrophage influx, which increase production of interleukin-1 and growth factor and chemokine release. These signal neutrophil chemotaxis, complement activation, and phagocytosis of crystals, leading to lysosome rupture and further tissue damage. Interestingly, in comparison to epidermal tophi inflammation, dermal and subcutaneous tophi inflammatory involvement is significantly reduced. 3. Interval or intercritical gout: The period between acute attacks, during which there are no symptoms and joint function is normal. 4. Chronic tophaceous gout: With prolonged hyperuricemia and acute episodes of gout, urate crystal deposits (tophi) may develop in the skin and soft tissues, synovial membranes, tendons, cartilage, and bone. In 20% to 30% of patients, uric acid renal stones will also form. Tophi usually develop 10 years or more after the onset of gout, but more rapid development is reported with myeloproliferative disorders and with deficiencies involving enzymes of purine metabolism. Tophi may resolve after 6 to 12 months of normouricemia. The differential diagnosis for acute gout includes pseudogout (chondrocalcinosis), osteoarthritis, psoriatic arthritis, Reiter s disease, septic joint, cellulitis, and traumatic injury. The tophi, which are yellow-white hard nodules, may mimic rheumatoid nodules, xanthomas, Heberden s and Bouchard s nodes, calcinosis cutis, or squamous cell carcinoma. The diagnosis of gout requires identification of urate crystals in joint fluid or within tophi, which appear as negatively birefringent, water-soluble, needleshaped crystals when viewed with polarized light. Tophi are radiolucent, but reports suggest that they can be identified by ultrasound (by virtue of the central non-sonotransmitting substance) and by in vivo Raman spectroscopy. Ultrasound can be used to differentiate tophi from rheumatoid nodules. Routine histologic examination of gout reveals amorphous, amphophilic material, with interspersed stellate cavities surrounded by giant cells, and lymphocytes forming chronic foreign-body granulomata. The cavities represent uric acid crystals that dissolved during standard processing in formalin or other water-based preservatives. In a clinical context suspicious for gout, tissue should be preserved in an alcohol-based fixative, such as Carnoy s fluid, or in 95% ethanol to allow retention of the urate crystals. Silver-based stains (Gomori s methenamine, De Galantha, or von Kossa) stain urate crystals dark brown to black. The management of acute gout is aimed at prompt reduction of inflammation and pain. The exquisitely sensitive affected areas should be routinely protected from trauma. Acute gout responds rapidly to nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and colchicine. NSAIDs are used as firstline agents because of their usually low side-effect profile. However, this is not the case in elderly patients, in whom NSAIDs have been associated with a high incidence of adverse systemic side effects. If NSAIDs are contraindicated, a short course of systemic corticosteroids (prednisone, methylprednisolone) may be administered. Single intramuscular doses of adrenocorticotropic hormone (ACTH) and triamcinolone acetonide have also been reported effective. Oral colchicine is used less frequently because of its greater toxicity profile, and risks of extravasation injury, bone marrow suppression, and renal, hepatic and nervous system toxicity are significantly increased during intravenous administration. Parenteral ketorolac or cyclooxygenase-2 (COX-2) inhibitors may prove effective for acute gout, although sufficient studies are not yet available. Allopurinol, a xanthine oxidase inhibitor, decreases uric acid production and is the drug of choice for urate over-producers, as well as in some patients with decreased urate excretion. It is most commonly employed in gout prophylaxis. Allopurinol blocks the conversion of hypoxanthine to xanthine, and subsequently to uric acid, rendering these components more soluble for renal excretion. In addition, allopurinol may be used to reduce de novo purine synthesis under normal metabolic conditions; however, it is not effective in patients with myeloproliferative disorders or hypoxanthine guanine phosphoribosyl transferase (HGPRT) deficiency. It is essential to prescribe low-dose NSAIDs when allopurinol is initiated to prevent acute attacks of gout. Drugs such as azathioprine and mercaptopurine are normally inactivated by xanthine oxidase. Inhibition of this enzyme by allopurinol can increase the toxic effects of these drugs, and dosages must be adjusted accordingly. A rash develops in approximately 2% of patients treated with allopurinol, and in 20% of patients receiving ampicillin and allopurinol concurrently. The most severe adverse effect of allopurinol is hypersensitivity, manifested by exfoliative dermatitis, fever, vasculitis, eosinophilia, liver dysfunction, and acute interstitial nephritis occurring in approximately 1/1000 patients.

5 190 Self-Assessment examination The uricosuric agents sulfinpyrazone and probenecid promote excretion of uric acid by inhibiting renal tubular reabsorption. The increase in urinary excretion of urate that occurs upon initiation of therapy can trigger the formation of renal uric acid precipitates. Uricosuric drugs are contraindicated in patients with low urine output, inadequate renal function (creatinine clearance \50 ml/min), or a history of renal calculi. The effects of probenecid, as well as the more potent sulfinpyrazone, are reversed by salicylate. The long-term management of gout involves treating hyperuricemia through risk modification and drug therapy. Secondary prevention should focus on modification of diet, weight loss, and reduction of alcohol intake. In general, a uricosuric drug is indicated in those with low urate clearance, and a xanthine oxidase inhibitor in patients with increased urate production. Many gout patients, however, have both low urate clearance and high purine intake or urate production. Emerging therapies for uric acid normalization have been stimulated by recent reports that the angiotensin II receptor antagonist losartan can reduce serum urate levels by increasing the fractional excretion of uric acid. In addition, a recombinant uricase could prove valuable in the treatment of patients with allopurinol hypersensitivity, coexisting renal failure, or tophaceous gout. The recent identification of URAT1, a renal urate-anion exchanger involved in serum urate regulation, may facilitate development of novel hypouricemic agents. For this series, the recommended choices are as follows: 9, e; 10, c; 11, a; 12, c; 13, a; 14, b; 15, d; 16, e; 17, d; 18, a; 19, c; 20, e; 21, a; 22, e; 23, b; 24, d; 25, b; 26, c; 27, b; 28, d. The authors thank Drs Norman A. Lockshin and Andrew H. Montemarano for their assistance. BIBLIOGRAPHY Emmerson BT. The management of gout. N Engl J Med 1996;334: Fam AG. Gout in the elderly. Clinical presentation and treatment. Drugs Aging 1998;13: Gerster JC, Landry M, Dufresne L, Meuwly JY. Imaging of tophaceous gout: computed tomography provides specific images compared with magnetic resonance imaging and ultrasonography. Ann Rheum Dis 2002;61:52-4. Touart DM, Sau P. Cutaneous deposition diseases: part II. J Am Acad Dermatol 1998;49: Weinberger A. Gout, uric acid metabolism, and crystal-induced inflammation. Curr Opin Rheumatol 1995;7: